Differential effects of lead and cAMP on development and activities of Th1- and Th2-lymphocytes

Lead (Pb) is known to have detrimental effects on the central nervous, hematopoietic, renal, and immune systems. Herein, it is demonstrated that Pb can skew T cell reactivities by preferentially enhancing the development of Th2 cells and inhibiting the development of Th1 cells. When naive splenic CD4+ T cells from DO11.10 ovalbumin-specific transgenic (OVA-tg) mice or OVA-tg/RAG2-/- mice were developed in vitro in the presence of Pb, preferential skewing toward Th2 cells was evident. The Pb-driven skewing toward Th2 was blocked significantly in the presence of exogenous IL-12 or anti-IL-4 mAbs. Although Pb and dibutyryl cAMP (dbcAMP) appear to have similar effects on the development and reactivity of Th1 cells, unlike Pb, dbcAMP did not enhance Th2 development/activity. Further evidence of Pb's differential T cell effects was observed, in that regardless of the activation stimuli (Ag/APC; anti-CD3; PMA + ionomycin), the addition of PbCl2 consistently resulted in significant inhibition of IFN gamma production by a Th1 clone and in increased IL-4 production by a Th2 clone. In vitro addition of IL-12 overcame Pb's inhibition of Th1 cells. Th1 cells treated with a phosphodiesterase inhibitor had significantly elevated [cAMP]i levels following anti-CD3 activation in the presence of Pb, suggesting that Pb may inhibit Th1 development by enhancing adenylate cyclase activity and elevating the [cAMP]i level. Similar to Pb, a low concentration (10 microM) of dbcAMP inhibited IFN gamma production by Th1, which was prevented by IL-12; however, inhibition of protein kinase A activity by KT5720 did not reverse these effects. These results indicate that the environmental toxicant Pb can modify immune reactivities by significantly altering the differentiation of precursor or naive Th cells as well as by directly inhibiting Th1 cells and stimulating Th2 cells.     

An imbalance between Th1 and Th2-like cytokines in patients with autoimmune diseases--differential diagnosis between Th1 dominant autoimmune diseases and Th2 dominant autoimmune diseases

An imbalance between T helper cell (Th)1 and Th2-like cytokines has been described in several autoimmune diseases. Organ specific autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel diseases (IBD) are caused by Th1 dominant immune responses. On the contrary, systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and Sj?gren's syndrome(SS) are characterized by Th2 dominant imbalance of cytokine production. It might be useful for differential diagnosis among patients with various autoimmune diseases such as SLE, SS, IBD, and MS to measure the serum levels of cytokines such as IL-10, IFN gamma, and TNF alpha using ultrasensitive enzyme-linked immunosorbent assay system.     

Preparation of recombinant gilthead seabream (Sparus aurata) growth hormone and its use for stimulation of larvae growth by oral administration

Optimal protective immunity against babesial infection is postulated to require both complement-fixing and opsonizing antibodies in addition to gamma interferon (IFN-gamma)-mediated macrophage activation. The rhoptry-associated protein 1 (RAP-1) of Babesia bigemina induces partial protective immunity and is a candidate vaccine antigen. Previous studies demonstrated that cattle immunized with native protein that were subsequently protected against challenge had a strong IFN-gamma and weaker interleukin-4 (IL-4) response in immune lymph node lymphocytes that reflected the cytokine profile of the majority of CD4(+) T-cell clones obtained from peripheral blood. RAP-1-specific T helper (Th) cell clones that coexpress IFN-gamma and IL-4 are typical of numerous parasite-specific clones examined. However, the function of such cells as helper cells to enhance immunoglobulin secretion by bovine B cells has not been reported. In cattle, both immunoglobulin G1 (IgG1) and IgG2 can fix complement, but IgG2 is the superior opsonizing subclass. Therefore, studies were undertaken to ascertain the functional relevance of RAP-1-specific, CD4(+) Th0 cells as helper cells to enhance IgG1 and/or IgG2 production by autologous B lymphocytes. For comparison, Th0 clones specific for the metazoan parasite Fasciola hepatica that expressed relatively more IL-4 than the B. bigemina-specific Th cells were similarly assayed. B. bigemina RAP-1-specific clones could enhance production of both IgG1 and IgG2 by autologous B cells, whereas Th cell clones specific for F. hepatica enhanced predominantly IgG1 production. The capacity to enhance IgG2 production was associated with production of IFN-gamma by Th cells cocultured with B cells, antigen, and IL-2. The in vitro helper T-cell activity of these T-cell clones was representative of the in vivo serologic responses, which were composed of a mixed IgG1-IgG2 response in B. bigemina RAP-1 immune cattle and a biased IgG1 response in F. hepatica-immune cattle.     

A role for T-helper type 1 and type 2 cytokines in the pathogenesis of various human diseases

Mosmann first proposed the existence of subsets of CD4+ T cells that produce distinct types of cytokines. Native T lymphocytes (Thp cells) differentiates into either CD4+ Th1 cells that produce IL-2, IFN gamma, and lymphotoxin which promote cell-mediated immunity, or into Th2 cells that produce IL-4, IL-5, IL-6, IL-10 and IL-13, which promote antibody production and humoral immunity. These T cell subsets reciprocally regulate one another since one of the Th1 products, IFN gamma, inhibits the proliferation and functions of Th2 cells, whereas the Th2 products, IL-4 and IL-10, suppress cytokine production by Th1 cells. A distinct Th1/Th2 divergence determine resistance versus susceptibility to diseases such as leishmaniasis and toxoplasmosis in mice. In allergic diseases such as atopic dermatitis and allergic asthma, allergen-specific T cells acquired the Th2 phenotype. These Th2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13. These cytokines induce eosinophilia and an Ig class switch to IgG4 and IgE. These Th2 cells are responsible for the enhanced production of IgE antibodies. These findings indicate that Th2 cytokines play an important role in the development of allergic diseases. The importance of cell-mediated immunity, particularly donor-anti-host CTL, in mediating acute GVHD suggests that Th1 cytokines may be important in the induction of acute GVHD. To further characterize the roles of Th1 and Th2 cytokines in the development of acute GVHD, analysis of IL-2, IFN gamma, IL-4 and IL-10 cytokine genes was performed by RT-PCR on biopsied skin specimen. An increase in mRNA expression for IL-2 and IFN gamma was observed, whereas there was no significant increase in IL-4 and IL-10 mRNA. These data suggest that Th1 cytokines may be essential for the development of acute GVHD. It is apparent that Th1 cytokines are generally harmful to the maintenance of pregnancy. We have shown that Th2 cytokines are produced by maternal T lymphocytes at the maternal-fetal surface (retroplacental blood lymphocytes). This finding strengthens the hypothesis of a significant contribution of Th2 cytokines to a successful pregnancy.     

Transplantation immunology: is the manipulation of the cytokine network therapeutically justified?

Classical allograft rejection is a cellular-mediated immune response in which the activation of the CD4+ T helper (Th) cell plays a crucial role. After activation the Th cell produces a variety of cytokines which are essential for initiating allograft rejection. Th cells can be distinguished by their cytokine profile. Th 1 cells produce IL-2 and IFN gamma, which are associated with rejection. Th2 cells are characterized by the production of IL-4 and IL-10, cytokines which are found in models when tolerance is induced. These findings are called the "Th1/Th2 paradigm" and lead to the following hypothesis: Th1 cells are responsible for allograft rejection and manipulation of the cytokine network towards a Th2 type cytokine pattern results in tolerance or delayed rejection. This study attempts to answer the question whether the Th1/Th2 paradigm is a pure association or corresponds to a mechanism which might be used therapeutically. Allograft rejection in the absence of the proinflammatory cytokines IL-2 and IFN gamma occurs almost unaltered. Moreover, supplying the anti-inflammatory cytokines IL-4 and IL-10 did not result in delayed rejection. Therefore, therapeutic manipulation of the very complex cytokine network will most likely fail. Blocking cytokine-independent T cell activation might be a better concept for induction of allograft tolerance.     

Sucrase-isomaltase and other brush border glycosidases in colorectal tumors

CD28 ligation delivers a costimulatory signal important in T cell activation. This study demonstrates that the disruption of the CD28/B7 pathway early in the nonobese diabetic mouse strain, using CD28-/- and CTLA41g transgenic mice, promoted the development and progression of spontaneous autoimmune diabetes. Functional analyses of T cells isolated from CD28-deficient mice demonstrated that the GAD-specific T cells produced enhanced Th1-type cytokines (IL-2 and IFN gamma) and diminished Th2-type cytokine, IL-4. Moreover, there was a significant decrease in serum levels of anti-GAD antibodies of the IgG1 isotype consistent with a profound suppression of Th2-type responses in these animals. Thus, the early differentiation of naive diabetogenic T cells into the Th2 subset is dependent upon CD28 signaling and extends our understanding of the importance of Th1/Th2 balance in the regulation of this spontaneous autoimmune disease.     

The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals

Interleukin (IL)-4-deficient mice were used to assess susceptibility to systemic or gastrointestinal Candida albicans infections, as well as parameters of innate and elicited T helper immunity. In the early stage of systemic infection with virulent C. albicans, an unopposed interferon (IFN)-gamma response renders IL-4-deficient mice more resistant than wild-type mice to infection. Yet, IL-4-deficient mice failed to efficiently control infection in the late stage and succumbed to it. Defective IFN-gamma and IL-12 production, but not IL-12 responsiveness, was observed in IL-4-deficient mice that failed to mount protective T helper type 1 cell (Th1)-mediated acquired immunity in response to a live vaccine strain of the yeast or upon mucosal immunization in vivo. In vitro, IL-4 primed neutrophils for cytokine release, including IL-12. However, late treatment with exogenous IL-4, while improving the outcome of infection, potentiated CD4(+) Th1 responses even in the absence of neutrophils. These findings indicate that endogenous IL-4 is required for the induction of CD4(+) Th1 protective antifungal responses, possibly through the combined activity on cells of the innate and adaptive immune systems.     

Engagement of the B lymphocyte antigen receptor induces presentation of intrinsic immunoglobulin peptides on major histocompatibility complex class II molecules

By means of the clonotypic variable region, the immunoglobulin (Ig) is a tumor-specific antigen on B cell neoplasms. We report that engagement of the B cell antigen receptor (BcR) promotes presentation of peptides derived from the B cell's intrinsic Ig to major histocompatibility complex (MHC) class II-restricted T cells. Thus, anti-Ig endowed normal, ex vivo B lymphocytes from H-2d, Ig constant heavy chain allotype b (IgCHb) mice with the capacity to stimulate an I-Ad-restricted T cell clone which recognizes the gamma 2ab 435-451 allopeptide. The corresponding self gamma 2aa peptide is cryptic and 6000-fold less antigenic than the gamma 2ab allopeptide. Even so, the syngeneic B cell lymphoma A20 which expresses surface(s) IgG2aa, was also recognized by the T cells after BcR ligation. Thus, anti-Ig triggered the disclosure of a cryptic tumor antigen determinant. We propose that autoantigens, by engaging the BcR of self-reactive B cells, induce presentation of intrinsic Ig peptides to which the T helper cell (Th) repertoire is not tolerant. In this way, B cells with anti-self potential may be activated without Th recognition of nominal autoantigen.     

IFN-gamma-secreting Th cells regulate both the frequency and avidity of epitope-specific CD8+ T lymphocytes induced by peptide immunization: an ex vivo analysis

CD8+ T lymphocytes are involved in protective immune responses to infected or tumor cells. In this report, we examined the regulation of antigen-specific CD8+ T cell frequency and avidity by distinct Th cell subsets. Peptide-specific CD8+ T cells were induced by immunization of mice with a MHC class I-restricted epitope, co-injected with a MHC class II-restricted epitope to recruit Th cells. CD8+ T cell responses were assessed directly ex vivo for lytic activity and IFN-gamma secretion using the enzyme-linked immunospot (ELISPOT) assay. Co-immunization in incomplete Freund's adjuvant (IFA) with three different helper peptides induced IFN-gamma- and IL-2-secreting Th cells, in the absence of IL-4 secretion, suggesting preferential Th1 profiles. Such immunization resulted in the increase of antigen-specific CD8+ T cell frequency, which was detected in blood as efficiently as in lymph nodes and spleen, and elicited high-avidity CD8+ T cells. We investigated whether these effects were dependent upon a particular Th profile. When alum was used instead of IFA, the production of IL-2 by Th cells was still significant, while the production of IFN-gamma was undetectable. Such Th cell activation failed to support an increase of antigen-specific CD8+ T cell frequency. Altogether, these results document in vivo the regulatory role played by Th cells in CD8+ T cell activation and may be relevant for the design of efficient vaccination schedules.     

Prevention of Crohn disease recurrence

Th1 cells, which produce IL-2 and IFN gamma, are responsible for cell-mediated immune responses, and Th2 cells, which produce IL-4 and IL-5, facilitate humoral immune responses. It has been shown that these two types of cells play critical roles in defensive immune responses and in immunopathological disorders such as allergic reactions and autoimmune diseases, and the methods of detecting Th1 and Th2 cells have become more important. A newly developed technique enables intracellular cytokines to be stained and detected on flow cytometry at a single-cell level. To show the existence of human Th1/Th2 cells, naive human CD4+ T cells were differentiated into Th cells in vitro, and Th1/Th2 cells were clearly demonstrated using intracellular IL-4 and IFN gamma staining. IL-4 promoted Th2 differentiation and IL-12 did Th1, as previously reported. Th1 and Th2 cells among human peripheral blood T cell population also can be detected by this technique using double staining for IL-4 and IFN gamma, and the predominance of Th1 cells among peripheral blood T cells were suggested. Measurement of intracellular cytokines is a useful technique, and will be used in the field of clinical laboratory medicine to further clarify the pathophysiology of immunological disorders.     

Prevention of experimental allergic encephalomyelitis via inhibition of IL-12 signaling and IL-12-mediated Th1 differentiation: an effect of the novel anti-inflammatory drug lisofylline

Experimental allergic encephalomyelitis (EAE) is an inflammatory, CD4+ Th1-mediated autoimmune disease, which serves as a model for multiple sclerosis. We examined the effect of a novel anti-inflammatory drug, lisofylline (LSF), on EAE induced either by injection of mouse spinal cord homogenate or following transfer of myelin basic protein-reactive T cells. Orally administered LSF significantly inhibited EAE in both cases, decreasing peak clinical scores by >70% and >80%, respectively. In addition, analysis of representative spinal cord sections from LSF-treated mice showed complete lack of demyelination and lymphocyte infiltration. The reduction in EAE correlated with the inhibition of Th1 differentiation by LSF in vivo, as indicated by a reduction in T cell IFN-gamma production ex vivo after Ag restimulation. The inhibition of Th1 differentiation in vivo is consistent with a block in IL-12 receptor signaling, because LSF blocked IL-12-driven Th1 differentiation and T cell proliferation in vitro, yet had no effect on IL-12 secretion from APCs ex vivo or in vitro.     

Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells

Evidence indicates that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. CD4(+) T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF-beta after antibody cross-linking of CTLA-4, indicating that induction of TGF-beta by CTLA-4 signaling represents a ubiquitous feature of murine CD4(+) T cells. Stimulation of the CD3-T cell antigen receptor complex does not independently induce TGF-beta, but is required for optimal CTLA-4-mediated TGF-beta production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon gamma (Th1) and IL-4 (Th2). Moreover, addition of anti-TGF-beta partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-beta1 gene-deleted (TGF-beta1(-/-)) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4(+) T cell production of TGF-beta, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-beta, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4(+) T cell activation.     

Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40-CD40 ligand interaction

The mechanism of IL-12 production has been studied by stimulating macrophages or B cell lines with LPS, Staphylococcus aureus, or phorbol diester. However, since IL-12 plays an important role in the activation of T cells interacting with APC, it is important to study the mechanism of IL-12 production induced by T helper cell-APC interaction. We and others have demonstrated that IL-12 is produced in cultures where Th1 cells are stimulated with Ag or APC. In the present experiments, we studied a role of CD40-CD40 ligand (CD40L) interaction in IL-12 production and obtained the following results: 1) incubation of normal Th1 clone with APC in the presence of Ag induced IL-12 p40 and p35 mRNA accumulation and IL-12 production, and the addition of anti-CD40L blocked the p40 mRNA accumulation and IL-12 production but not p35 mRNA accumulation; 2) when Th1 clone from a CD40L-deficient mouse was used in the incubation, p35 mRNA accumulation was induced, but neither p40 mRNA accumulation nor IL-12 production was induced; 3) CD40L+ Th1 clone, or insect cell membrane expressing mouse CD40L, induced p40 mRNA accumulation and IL-12 production but not p35 mRNA accumulation. These results indicate that the CD40-CD40L interaction plays a critical role in IL-12 p40 mRNA accumulation and bioactive IL-12 production and that p35 mRNA accumulation was regulated via a different mechanism than CD40-CD40L interaction. Most of the cells producing IL-12 were Mac-1+ macrophages.     

Murine leishmaniosis: a paradigm for the importance of T helper 1 and T helper 2 cells

The murine model of leishmaniosis is a prototypic example for the critical role played by T helper cells in immunity to pathogens. Cytokines, such as interleukin-12 and interleukin-4, are the major regulatory factors for differentiation of naive T helper cells into T helper 1 and T helper 2 cells, respectively. T helper 1 cells, which are cellular immune mechanisms involving gamma interferon production, are associated with protection against murine leishmaniosis. Loss of T helper 1 activity (i.e., reduced gamma interferon production and lack of macrophage activation) leads to a fatal progressive course of murine leishmaniosis. Knowledge of the murine model of leishmaniosis is now contributing to studies of infectious diseases in humans, livestock and companion animals. Greater insight into the pathogenesis, diagnosis and therapy of infectious diseases will be gained from the analysis of cytokine-dependent regulation of T helper responses during infection. In particular, the development of prophylactic and therapeutic vaccines will benefit significantly from these studies.     

Single-cell analysis of intrathyroidal lymphocytes shows differential cytokine expression in Hashimoto's and Graves' disease

Most human organ-specific autoimmune diseases such as Hashimoto's thyroiditis (HT) are considered to be Th1 mediated, and a quantitative dominance of Th1 cells in thyroid infiltrates from both Graves' disease (GD) and HT affected glands has been reported. However, Th2 dominance would be expected in GD, where thyroid hyperfunction induced by stimulating antibodies predominates over tissue destruction. We have analyzed the interleukin-4 (IL-4), interferon-gamma (IFN-gamma) production by T cells at the single-cell level, both in infiltrating lymphocytes isolated from digested GD and HT thyroid glands and in derived T cell lines, by direct intracellular cytokine detection. Results showed a heterogeneous pattern of cytokine production in bulk GD infiltrates and derived T cell lines, and a similar pattern was observed in the much larger HT infiltrates. Both type 1 and type 2 cytokines were simultaneously produced by the infiltrating populations, and T cells with both patterns as well as intermediate patterns similar to Th0 cells could be detected ex vivo. However, the larger T lymphocytes, presumably activated and responsible for the autoimmune damage, predominantly produced IL-4 in GD and IFN-gamma in HT. The specificity of the Th2 responses in GD was suggested by the enrichment in IL-4 production after antigen-specific expansion of two oligoclonal T cell lines. These data show that both type 1 and type 2 cytokines are produced in the thyroid glands affected by autoimmunity and that the difference between diseases may be the effect of a functionally dominant population at a given time. This in vivo chronically activated antigen-specific population, producing type 1 or type 2 cytokines locally, may be responsible for the effect finally leading to one of the disease states.     

T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function

T helper (Th) cells can be categorized according to their cytokine expression. The differential induction of Th cells expressing Th1 and/or Th2 cytokines is key to the regulation of both protective and pathological immune responses. Cytokines are expressed transiently and there is a lack of stably expressed surface molecules, significant for functionally different types of Th cells. Such molecules are of utmost importance for the analysis and selective functional modulation of Th subsets and will provide new therapeutic strategies for the treatment of allergic or autoimmune diseases. To this end, we have identified potential target genes preferentially expressed in Th2 cells, expressing interleukin (IL)-4, IL-5, and/or IL-10, but not interferon-gamma. One such gene, T1/ST2, is expressed stably on both Th2 clones and Th2-polarized cells activated in vivo or in vitro. T1/ST2 expression is independent of induction by IL-4, IL-5, or IL-10. T1/ST2 plays a critical role in Th2 effector function. Administration of either a mAb against T1/ST2 or recombinant T1/ST2 fusion protein attenuates eosinophilic inflammation of the airways and suppresses IL-4 and IL-5 production in vivo following adoptive transfer of Th2 cells.     

An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus

Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that beta-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF alpha, and IFN alpha) and type 1 cytokines (IFN gamma, TNF beta, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF beta). Cytokines (IL-1, TNF alpha, TNF beta and IFN gamma) may be directly cytotoxic to beta-cells by inducing nitric oxide and oxygen free radicals in the beta-cells. In addition, cytokines may sensitize beta-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the beta-cells (an action of IFN gamma), and inducing Fas (CD95) expression on beta-cells (actions of IL-1, and possibly TNF alpha and IFN gamma). Transgenic expression of cytokines in beta-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN alpha, IFN gamma, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF alpha. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN gamma-producing), but other islet-specific Th1 clones that produce TGF beta can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN gamma genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN gamma, also IL-1, TNF alpha, IL-2, and IL-6--by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs--significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development.     

Regulation of CD4 T cell reactivity to self and non-self

While the thymus may be effective in inducing tolerance to lymphoid associated antigens, it is not as efficient in deleting T cells reactive to peripheral tissue specific antigens. Therefore, to maintain self tolerance to peripheral tissues, post-thymic mechanisms must be invoked. One important way to prevent autoimmune pathology mediated by autoreactive CD4 T cells is the diversion of clones to regulatory Th2 effector cells. However, many different factors contribute in vivo to the decision of stimulated CD4 T cells to develop into Th1 versus Th2 cells. For example, T cell signaling pathways may influence the types of cytokines produced by naive T cells, and studies have provided evidence for a genetic polymorphism among common mouse strains that can significantly influence the early cytokine production in stimulated naive CD4 T cells. The allele carried by the BALB/c strain promotes IL-4 production, and consequently provides resistance to autoimmune diabetes in our transgenic mouse model. In addition, antigen presenting cells can influence the development of stimulated CD4 T cells in part through the production of cytokines such as IL-12. The absorption of IL-12 in vivo can permit the expansion of Th2 type effector cells, and this phenomenon will also protect mice from autoimmunity. Finally, the relative potency of various class II positive antigen presenting cell types can influence the development of autoreactive T cells, with dendritic cells apparently being the strongest stimulator of Th1 responses. Consistent with this notion, a relB knockout mouse, which is missing dendritic cells, appears to drive Th2 development even in response to viral infection. In sum, these various influences over the Th1/Th2 decision in vivo may provide new targets for immunotherapy of autoimmune diseases.